Dias Luiza R S, Santos Marcelo B, Albuquerque Sérgio de, Castro Helena C, de Souza Alessandra M T, Freitas Antônio C C, DiVaio Maria A V, Cabral Lucio M, Rodrigues Carlos R
Universidade Federal Fluminense (UFF), Laboratório de Química Medicinal (LQMed), Faculdade de Farmácia, Rua Mário Viana, 523, Santa Rosa, 24241-000, Niterói, RJ, Brazil.
Bioorg Med Chem. 2007 Jan 1;15(1):211-9. doi: 10.1016/j.bmc.2006.09.067. Epub 2006 Oct 1.
The development of new drugs against Trypanosoma cruzi is still required since the only two drugs currently used cause severe side effects. In this work we described the synthesis, the in vitro biological evaluation, and the SAR results of 1H-pyrazolo[3,4-b]pyridine derivatives, a new antichagasic agent series. The presence of fluorine, hydroxyl or nitro group at Y position resulted in at least one or two promising compounds in each set of derivatives (6f, 6g, 6i, 6l, and 6m). The SAR study showed that trypanocidal activity observed depends on both geometric and stereoelectronic parameters (MEP and frontier molecular orbitals HOMO and LUMO). We also used the Osiris program for calculating and comparing the fragment based druglikeness of the most active derivative (6g) (IC(50)=1.9microg/mL), the inactive compound (6o), and the current toxic antichagasic drugs (nifurtimox and benznidazole). Interestingly 6g presented a potential druglikeness higher than nifurtimox and benznidazole while 6o presented the lowest value among them.
由于目前仅有的两种药物会引发严重的副作用，因此仍需要研发针对克氏锥虫的新型药物。在这项工作中，我们描述了新型抗恰加斯病药物系列1H-吡唑并[3,4-b]吡啶衍生物的合成、体外生物学评估以及构效关系（SAR）结果。在Y位存在氟、羟基或硝基会在每组衍生物（6f、6g、6i、6l和6m）中产生至少一种或两种有前景的化合物。构效关系研究表明，所观察到的杀锥虫活性取决于几何和立体电子参数（分子静电势和前沿分子轨道HOMO和LUMO）。我们还使用奥西里斯程序计算并比较了活性最高的衍生物（6g）（IC(50)=1.9μg/mL）、无活性化合物（6o）以及当前有毒的抗恰加斯病药物（硝呋替莫和苯硝唑）基于片段的类药性质。有趣的是，6g的潜在类药性质高于硝呋替莫和苯硝唑，而6o在它们当中类药性质最低。
